Around and beyond 53BP1 Nuclear Bodies

Abstract

Within the nucleus, sub-nuclear domains define territories where specific functions occur. Nuclear bodies (NBs) are dynamic structures that concentrate nuclear factors and that can be observed microscopically. Recently, NBs containing the p53 binding protein 1 (53BP1), a key component of the DNA damage response, were defined. Interestingly, 53BP1 NBs are visualized during G1 phase, in daughter cells, while DNA damage was generated in mother cells and not properly processed. Unlike most NBs involved in transcriptional processes, replication has proven to be key for 53BP1 NBs, with replication stress leading to the formation of these large chromatin domains in daughter cells. In this review, we expose the composition and organization of 53BP1 NBs and focus on recent findings regarding their regulation and dynamics. We then concentrate on the importance of the replication stress, examine the relation of 53BP1 NBs with DNA damage and discuss their dysfunction.

Keywords: 53BP1; DNA damage; cancer; common fragile sites; genetic instability; nuclear bodies; replication stress.

Figure 1

Composition of 53BP1 nuclear bodies. Unreplicated DNA from mother cell (red area) induces the accumulation of DDR signaling factors in G1 daughter cells (53BP1 (red), MDC1, MRN complex, ATM (brown), RNF8, RNF168 (green) and BRCA1 (blue), associated with histone H2A/H2AX ubiquitinylation (green U chains) and H2AX phosphorylation, i.e., γH2AX (yellow circled P on nucleosomes). This in turn locally alters chromatin structure through the recruitment of the insulator protein CTCF (light blue) and enhances chromatin compaction mediated by SPOC1 (yellow) and HP1 (blue). Exclusion from 53BP1 NBs of RNA Pol II and DNA repair factors locally inhibits transcription and DNA repair, respectively.

Figure 2

General scheme of 53BP1 NBs formation. During S phase, difficult to replicate loci such as common fragile sites (CFS) and direct DNA damage induce physiological replication stresses responsible of under-replicated DNA, allowing cells to escape checkpoint activation and reach mitosis. As cells enter mitosis, SLX4-MUS81-EME1 complexes cleave under-replicated loci to initiate mitotic DNA synthesis (MiDAS). In absence of sister chromatids decatenation by BLM-TopoIII-RMI1-RMI2 (BTR complex)-TOP2 at MiDAS sites, bulky anaphase bridges (DAPI+) are formed. Incomplete resolution of late replication intermediates through MiDAS induces bulky bridges and DNA ultra-fine bridges (UFBs) formation at anaphase. UFBs resolution by BTR-PICH constitutes the last chance for rescuing partially replicated DNA stretches before the end of anaphase. Impairing faithful resolution of UFBs leads to 53BP1 NBs in G1 daughter cells, whereas a direct link between bulky bridges and 53PB1 NBs is controversial (arrow with question mark). Alternatively, under-replicated regions that are not associated to UFBs may also generates 53BP1 NBs. 53BP1 NBs-positive daughter cells enter in quiescence and/or exhibit a prolonged G1 before reaching S phase. 53BP1 NBs dissolution occurs in early-mid S phase through a process that still need to be elucidated. T bars on the scheme mean that the process is negatively regulated.